Stimulating the Hunt for Asthma Genes

In the recent kerfuffle over the national debt, one of the rhetorical flashpoints was the $800 billion “stimulus package” pushed by the Obama administration in 2009 to fight the economic slowdown. Though the benefits of the American Recovery and Reinvestment Act on unemployment and the economy are fiercely debated, the impact upon the scientific world is just beginning to be felt. Roughly $5 billion of the stimulus money went to the National Institutes of Health for funding biomedical research – and $42 million of that sub-total came to projects involving University of Chicago researchers. Two years later, the fruits of that investment are beginning to ripen, as stimulus-funded projects reach the point of publishing results.

The largest piece of the stimulus pie awarded to UChicago researchers was the $5.6 million designated to form the EVE consortium, an unprecedented national effort to search for the genetic and environmental causes of asthma. Over 34 million Americans are diagnosed with asthma during their lifetime, and the rates are increasing every year. But the origins of this respiratory disease are still mysterious, with the relative contributions of genetics and environmental factors such as air quality and smoking still being unraveled.

One recent tool in decoding the causes of asthma has been genome-wide association studies, or GWAS, where genetic information from a large pool of patients with the disease are compared to a control pool of asthma-free people. But to find a gene or gene variant associated with a complex disease like asthma, a huge number of subjects are needed for statistical reasons. The expenses of successfully recruiting, diagnosing, and genotyping the thousands of people needed to create a sufficiently powerful GWAS were beyond the means of any one research group, frustrating the search for asthma-related genes.

“It has become clear to geneticists studying nearly every common disease that GWAS are often under-powered,” said Carole Ober, Blum-Riese Professor of Human Genetics and obstetrics/gynecology at the University of Chicago. “Unless you pull together many people doing the same thing you’re just not going to have the power to find genes.”

In the world of asthma genetics, nine groups of investigators were encouraged by the National Heart, Blood, and Lung Institute to pool their respective GWAS results to create a shared pool of data large enough to sniff out genes associated with the disease. But that collaboration was easier said than done – until the $5.6 million ARRA grant enabled the hiring of personnel to make the EVE consortium a reality.

“It would never have been possible without the grant, this was a huge amount of work,” said Dan Nicolae, PhD, associate professor of medicine, statistics, and human genetics at University of Chicago, and co-chair of the consortium with Ober. “The key was the ARRA funding that allowed us to move it faster.”

Now, just short of two years since the grants were announced, the EVE consortium has announced their initial results in the journal Nature Genetics. With a new larger data set of over 5,000 asthma cases, the group was able to pinpoint with high accuracy five genetic regions associated with asthma, including one with a very selective profile. Unlike a similar consortium formed in Europe (called GABRIEL), the EVE dataset reflected the ethnic diversity of the American melting pot with subjects of European origin, African origin, and Hispanics. That diversity proved useful, as the EVE data revealed an asthma-associated variant in a gene called PYHIN1 that only appeared in African-Americans and African-Caribbeans – ethnic groups not present in the GABRIEL sample published last year.

“Asthma rates have been on the rise in recent years, with the greatest rise among African Americans,” said Susan B. Shurin, acting director of the National Heart, Lung, and Blood Institute, which co-funded the study. “Understanding these genetic links is an important first step towards our goal of relieving the increased burden of asthma in this population.”

In the four gene variants where the GABRIEL and EVE agreed, the diverse subject pool was again important. By proving them twice in two samples, the variants – located in the the 17q21 locus and IL1RL1, TSLP, and IL33 genes – were shown to be relevant to asthma in all ethnic groups, not just the European groups studied in the GABRIEL data. That’s an important vote of confidence for researchers looking to further study these genes to determine why they increase the risk of asthma, as well as how they might be turned around to prevent or treat the disease.

“We really now have a really good handle on at least five genes that anyone would be comfortable saying are asthma risk loci,” Ober said. “I think it’s an exciting time in asthma genetics.”

When the ARRA grant ends later this year, the EVE consortium will not disappear with it, Ober and Nicolae said. Now that the infrastructure of the collaboration has been built, further high-powered investigations can take place with the data, including a deeper GWAS meta-analysis currently underway. The individual laboratories are also spinning off their own projects using the power of the pooled data, looking for associations between gene variants and more specific symptoms of asthma, or adding in environmental factors to study gene-environment interactions. Long after the debate in Washington over the success of the stimulus fades, the research ripples from the burst of scientific funding will still be spreading.

“What you see here in this paper is only the beginning,” Nicolae said. “The foundation was to make people work together, share the data, and share research ideas, and that will generate a lot of research down the road.”